Stroke is the third leading cause of mortality in the United States and the largest single cause of adult disability. Intravenous tissue plasminogen activator (t-PA) is the only Food and Drug Administration (FDA) approved acute drug therapy for ischemic stroke and must be administered within three hours of symptom onset and after intracerebral hemorrhage has been excluded. Primarily due to this short time window for treatment, thrombolytic therapy is used in less than 2% of all hospitalized stroke patients. The interruption of cerebral perfusion during stroke initiates a cascade of detrimental events that may ultimately lead to cell death. This process occurs via multiple pathways but no clear final pathway has been identified. Previous neuroprotection strategies have focused on targeting single pathways. However, an "ideal" neuroprotectant should favorably influence multiple pathways, should be safe and well tolerated, and should have a long therapeutic time window. Carnosine, a dipeptide, is an endogenous antioxidant and a popular dietary supplement with no known side effects or adverse interactions with other drugs. Considerable data suggest that it may also favorably influence multiple deleterious pathways that are activated in stroke and it appears to robustly protect in an animal model of stroke. Based on these data, carnosine appears to be an excellent candidate as a therapy for stroke. However, before clinical testing can take place, rigorous and extensive preclinical pharmacokinetic, safety and efficacy data are required. These data are not available at this time. The aims of this project are to generate pre-clinical pharmacokinetic, efficacy and safety data for the use of carnosine as a neuroprotective therapy in stroke. The rat model of transient and permanent ischemia will be used for both toxicity and efficacy studies. These data will be used to plan more detailed preclinical studies that will allow eventual testing in humans. The long term goal is to develop a new safe and effective stroke therapy that will benefit far more people than the currently available therapy. Stroke is one of the leading causes of death and disability in the United States. The only approved FDA therapy must be administered within three hours of symptom onset but most stroke victims are not eligible for this treatment because they arrive in hospital too late. The goal of this project is to evaluate pre-clinically, a safe, innovative and promising natural drug called carnosine, because it has produced excellent results in early preclinical stroke studies and has the potential to benefit many more stroke patients.